Emerging Patterns and Current Trends of AIDS Dening and Non-AIDS Dening Malignancies in HIV Infected Individuals from a Tertiary Care Center in South India

Background: People living with HIV/AIDS are at increased risk of developing malignancies- both AIDS dening and non-AIDS dening. The trends in incidence and severity of cancers among those with HIV/AIDS has greatly changed since the advent of ART. The aim of this study was to analyse the clinico-epidemiological prole of patients in South India with HIV/AIDS who subsequently developed malignancy. Methods: A retrospective study was conducted by reviewing the medical records of patients with HIV/AIDS who were diagnosed with cancer after seroconversion from January 2014 to December 2019 and presented to a tertiary medical centre. Results: Of the 627 cases of HIV presenting to the hospital during the study period, 50 (8%) developed cancer. Among the patients with cancer 14 (28%) had AIDS dening cancer while 36 (72%) had non- AIDS dening cancer. The mean CD4 cell count at the time of diagnosis with malignancy was 502.45/uL. Among the patients with AIDS dening malignancies, 10 patients (71.4%) had NHL, 3 patients (21.4%) had invasive cervical cancer and one patient (7.1%) was diagnosed with CNS lymphoma. Among the 36 cases of non-AIDS dening malignancies, there were 7 cases (19.4%) of malignancies of the upper airway (oral cavity, nasopharynx, larynx), 7 cases (19.4%) of malignancies of the female genital tract, 6 cases (16.7%) of haemato-lymphoid malignancies, 3 cases each (8.3%) of malignancies of the lung and GIT including anal canal. 2 cases each (5.6%) of breast carcinoma or carcinoma of the male genital tract. 1 case each (2.8%) of cancers of the eye, urinary tract and metastatic lesion with an unknown primary were also reported. Conclusion: Malignancies in HIV infected individuals in an emerging global health issue. In the present study, we report a prevalence of 8% of malignancies in HIV infected individuals and a higher incidence of non-AIDS dening malignancies.


Introduction
HIV is a major global pandemic with high morbidity and mortality. The World Heath Organisation (WHO) estimates that around 38 million people are presently living with HIV, which include breastfeeding mothers and children. Worldwide, there have been around 6,90,000 deaths attributable to HIV. 1,2 In India, although current trends show a decline, there is still a signi cant 23.48 lakh population living with HIV and 69.22 thousand newly diagnosed cases every day. 3 The development of Anti-Retroviral Therapy (ART) substantially reduced mortality rates in HIV infected individuals. 4 However, this increased longevity had nonetheless led to other challenges, namely, development of other complications including malignancies, opportunistic infections and cardiovascular diseases in this cohort of patients, that may be attributable to either ART or due to HIV infection itself. 5 Traditionally, malignancies in HIV infected individuals have been classi ed into AIDS-de ning (Non-Hodgkin lymphoma, Kaposi sarcoma, cervical carcinoma) and non-AIDS de ning malignancies. 22 It is increasingly observed that there is a changing trend with development of non-AIDS de ning malignancies in the HIV-infected individuals who are receiving ART therapy, as compared to the AIDS-de ning malignancies such as Kaposi's sarcoma and Non-Hodgkin lymphoma (NHL) that were traditionally reported in the pre-ART era. It has been reported that HIV infected individuals are at an increased risk for Non-AIDS de ning malignancies such as Hodgkin lymphoma (HL), anal carcinomas and lung carcinomas. Few studies have described the survival outcomes of HIV infected individuals with malignancies and have observed a poorer outcome in them. 6 Although the rates of opportunistic infections have declined with introduction of ART, they still remain an important cause of mortality in HIV infected individuals, particularly due to late detection as well as lower CD4 cells counts.. These include Pneumocystis jiroveci, toxoplasma, candida, tuberculosis and cryptococcus. 7 Human Papilloma Virus (HPV) leading to Kaposi's sarcoma, non-Hodgkin lymphoma, cervical and anal carcinomas respectively. 9 Estimation of CD4 cell count re ects the immune status of the individual, and is used in the management and prognosis of HIV. With the natural progression of disease, there is a decline in CD4 cell counts that heightens the risk for malignancies, cardiovascular disease and opportunistic infections. Moreover, a low CD4 cell count has also been seen to precede a diagnosis of Hodgkin lymphoma. 10 Majority of studies on the prevalence of AIDS de ning as well as non-AIDS de ning malignancies are from Western Literature. There is paucity of literature of AIDS related cancers from India, despite being having one of largest global burden of HIV/AIDS. Knowledge about patterns and emerging trends of cancers in HIV patients may provide crucial insight into the pathobiology of HIV and may be of vital importance in prediction, risk strati cation, screening, early detection and management of cancers in HIV infected individuals. 11,12 The aim of the present study is to study the emerging patterns and current trends of AIDS de ning and non-AIDS de ning malignancies in HIV infected individuals.

Materials And Methods
The present study is a retrospective study conducted in the Department of Pathology at Kasturba Medical College, Mangalore from January 2014 to December 2019. Institutional Ethics committee clearance was obtained prior to the commencement of the study. All cases of HIV infected individuals in the study period who were subsequently diagnosed with cancer following seroconversion were included in the present study. The patients without a documented HIV positive test, those with cancer prior to HIV seroconversion and patients without histopathological con rmation of malignancy were excluded from the present study.
In selected cases, the demographic data, clinical history, examination ndings and treatment details, relevant laboratory investigations including HIV viral loads, CD4 lymphocyte counts, serum tumour markers, cytology reports, radiological investigations and histopathology reports were recorded from the patients' case les. The results thus obtained was tabulated and analyzed. Statistical analysis was performed by SPSS software, version 18.

Results
The present study included 627 HIV patients who visited the hospital during the study period. The age of the patients ranged from 1 to 75 years with a mean age of 42.9 years. Of the 627 patients, 382 patients were male (n = 627, 60.9%) and 245 patients were women (n = 627, 39.1%).

ART therapy:
Of the total patients, 403 patients were on ART (64.3%), with 356 patients (56.8%) on rst line ART and 47 patients (7.5%) on second line ART. Of the 356 patients on 1st line ART, 24 patients (6.7%) subsequently developed cancer whereas among the 47 patients on second line ART, 3 (6.3%) developed cancer. 121 patients (19.3%) patients who visited the hospital did not receive ART. Of these patients 21(17.35%) went on to develop cancer. 10 (1.6%) patients discontinued treatment after initiating ART; among them 2 patients (20%) went on to develop cancer.
The demographic data of the HIV patients with malignancy is depicted in Tables 1 and 2.  Treatment modalities: The most common treatment modality for those patients with cancer and HIV was chemotherapy which was received by 13 patients (26%), followed by surgery which was performed for 9 patients (18%), and concurrent chemo-radiation in 7 patients (14%).
AIDS de ning malignancies: The mean age of patients with AIDS de ning malignancies was 45.14 years (Age range: 7-67 years). Of these patients, 8 (57.1%) were male and 6 (42.9%) were female. 9 patients (64.3%) were diagnosed with a malignancy within the rst 5 years of being diagnosed with HIV. There was 1 case of metastatic renal cell carcinoma.
There were 2 cases of squamous cell carcinoma of the penis. There were 7 cases of carcinomas of the female genital tract, of which 3 (42.9%) were cases of noninvasive cervical carcinoma, 2 cases (28.6%) of ovarian carcinoma and 2 cases (28.6%) of endometrial stromal sarcoma.
Among the malignancies of the breast, there were 2 cases of in ltrating ductal carcinoma.
There was 1 case of metastasis with an unknown primary and 1 case of an ocular surface squamous neoplasm.
HPV linked and non-HPV linked malignancies: and other investigations as well as potential treatment options. However, patient party wanted to undergo further treatment in their hometown. Hence, the child was given nutritional supplementation and discharged.
There were no cases of any malignancies among young adults of age group 18-25 years.

Discussion
HIV infected individuals are at an increased risk of developing cancer. 13 In the early 1980's, reports of a cluster of cases of Pneumocystis jiroveci and an unusually aggressive malignancy, Kaposi's sarcoma in homosexual men drew attention to the rising AIDS pandemic. It soon spread throughout the globe and soon worldwide, there were increasing reports of certain speci c cancers namely Kaposi's sarcoma, aggressive lymphomas and cervical cancers, which have now been termed as AIDS de ning cancers. The discovery of Kaposi Sarcoma Herpes viruses that was responsible for development of Kaposi's sarcoma, led to the understanding of the oncogenic potential of other viruses including the Epstein Barr virus and Human Papilloma viruses. 9 The present study included 627 HIV infected patients which included 50 cases of patients with HIV and malignancy. The majority of the patients were male and the mean age was 42.9 years. In a study by Venkatesh et al, the authors studied 42 patients with HIV and malignancy, in which majority of the patients were male. The mean age of the patients in the study was 35 years. These ndings were similar to the present study. 11 The prevalence of malignancies in patients with HIV in the present study was found to be 8%. In a study done in Guinea, Traore  In the present series, majority of the patients (72%) had a non-AIDS de ning malignancies similar to the nding by Traore et al 25 . The cases in the present study included malignancies of the oral cavity, nasopharynx, larynx, female genital tract, haematolymphoid malignancies, lung, GIT including anal canal, breast carcinoma, male genital tract, eye, urinary tract and metastatic lesion with an unknown primary.
HIV infected individuals have a two to four times higher risk of head and neck carcinomas and double the risk of oral cavity and pharyngeal carcinomas as cancer compared to HIV un-infected individuals. This may be attributable to HPV with studies showing a prevalence of oncogenic HPV ranging from 12-26% among HIV infected individuals. Of the various subtypes, HPV 16 has been implicated in over 80% of malignancies of the oropharynx. 24 There were 3 cases each of anal carcinomas, cervical carcinomas, multiple myelomas, lung and GIT excluding the anus.
In a study done in Guinea, authors reported that breast cancer was the most common non-AIDS de ning malignancy, while lung malignancy was more common in developed countries, in contrast to the present study, where we found a lower incidence of both these malignancies. In another study by Venkatesh et al, the researchers found Hodgkin's lymphoma to be the most frequent malignancy among the non-AIDS de ning malignancies, followed by breast carcinomas (11) .
The AIDS de ning malignancies accounted for only a minority of cases in the present study (28%).
Among these, the most common was NHL, followed by cervical cancers. These ndings were similar to that reported by Venkatesh et al and Traore et al (11,25) .
There were no reported cases of Kaposi's sarcoma in the present study. This was similar to ndings reported by Phatak et al. The authors noted that AIDS de ning cancers including Non-Hodgkin lymphoma and cervical carcinomas, were seen in 54.35% cases whereas non-AIDS de ning cancers were noted in 45.65% cases. The authors too did observe Kaposi's sarcoma in their study. This was in contrast to another study from Nigeria that have found increased risk of development of Kaposi's sarcoma but neither Non-Hodgkin lymphoma or cervical carcinomas among HIV infected patients. This highlights signi cant demographic differences with respect to malignancies among HIV infected individuals in different parts of the world. 17,18 Among the malignancies, 16 patients (32%) had HPV linked malignancies, while 34 patients (68%) had non-HPV linked malignancies. Studies have reported a high incidence and prevalence of association of HPV as well as precursor lesions in patients with HIV as compared to the general population. These includes ano-genital malignancies including cervical carcinomas and anal carcinomas. Authors have reported that the risk of anal carcinomas is higher in homosexual men and have recommended screening the at-risk population. Similarly, current guidelines for HIV infected women recommend cytology screening once in every six months for 2 consecutive negative cytology results and thereafter yearly.
Researchers have recommended colposcopic examination with acetic acid for cervical carcinoma screening in resource strapped countries to reduce the incidence of these cancers (26) .
The risk of HPV related malignancies at other sites including oropharynx, penis, vulva, vagina have also been predicted to be increased although at present, data is limited with regard to these. 19,20 Presently, cancer screening plays a crucial role in the routine management of patients living with HIV, which would include an assessment of individual risk, survival, risks and bene ts of screening as well as its potential outcome. Although the successful intervention in the form of cancer screening in general population has proved bene cial, data on similar intervention in HIV infected individuals is lacking. Sigal et al. provided a conceptual framework of screening for cancer in patients with HIV. This included a Pap test for cervical carcinomas, anal cytology test for anal carcinomas, abdominal ultrasound and AFP estimation for hepatocellular carcinomas. In addition to these, other screening modalities including mammography for breast carcinoma, fecal occult blood testing and sigmoidoscopy for colonic carcinoma, PSA test for prostatic carcinoma, CT scans in heavy smokers for lung carcinoma have been recommended by other authors. 21 There was 1 case of malignancies in a child and no cases of malignancies in young adults. Researchers have reported highest frequency of Kaposi's sarcoma, NHL and leiomyosarcoma in the young. However, the child in our study had Non Hodgkins Lymphoma.
Yet another study by Dhokotera et al. studied 1853 cases of adolescent and young patients of HIV with malignancies and found maximal cases of Kaposi sarcoma, cervical carcinoma, Hodgkins lymphoma and anogenital carcinomas other than cervix.
Researchers have documented higher incidence of malignancies caused by oncogenic viruses attributable to high risk behavior in sexually active adolescents and adults such as cervical carcinomas, anogenital carcinomas and hepatocellular carcinomas. There remains a higher risk in those individuals who have perinatally acquired HIV infection, attributable to various factors including longer duration of infection with HIV, immune dysregulation and co-infection with HBV, HCV or both. Thus it is recommended that this unique cohort of young patients must be diagnosed at the earliest and started on ART therapy and that access to HPV and HBV vaccination as well as individualized cancer screening facilities should be provided in their multidisciplinary services. 22,23 Conclusion Malignancies in HIV infected individuals in an emerging global health issue, particularly in young patients. In the present study, we report a prevalence of 8% of malignancies in HIV infected individuals and a higher incidence of non-AIDS de ning malignancies. A multidisciplinary approach for early detection, along with initiation of ART therapy, access to vaccination and cancer screening facilities is recommended for HIV infected individuals. The following study has been approved by the Institutional Ethics Committee.

Consent form available
Availability of data and materials The dataset analyzed during the current study is available from the corresponding author on reasonable request.

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Funding None Authors' contributions Authors contributed to the manuscript in the following ways: study concept and design (CSP,SRS,RM); acquisition, analysis, and interpretation of the data (CSP,SRS,JTR,SR,RM); drafting the manuscript (CSP,SRS); critical revision of the manuscript for important intellectual content (all authors); statistical analysis (CSP,SRS); administrative, technical, or material support (all authors); and study supervision (all authors). All authors have read and approved the nal manuscript.